E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne Muscular Dystrophy |
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E.1.1.1 | Medical condition in easily understood language |
An inherited disease causing muscle degeneration. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013801 |
E.1.2 | Term | Duchenne muscular dystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate changes in leg MRI in paediatric patients with DMD, following treatment with SMT C1100(cohorts 1 and 2 )
To investigate the relationships between changes in leg MRI with plasma concentrations of SMT C1100 and its metabolites in paediatric patients with DMD, following treatment with SMT C1100 (cohorts 1 and 2)
To assess the safety and tolerability of SMT C1100 and its metabolites in paediatric patients with DMD |
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E.2.2 | Secondary objectives of the trial |
To investigate changes in utrophin expression and muscle fibre regeneration in muscle, in paediatric patients with DMD, following treatment with SMT C1100 (cohorts 1 and 2 ) To investigate the relationships between changes , utrophin expression and fibre regeneration in muscle and safety parameters with plasma concentrations of SMT C1100 and its metabolites in paediatric patients with DMD, following treatment with SMT C1100 (cohorts 1 and 2 ) To investigate changes in pulmonary function tests in paediatric subjects with DMD, following treatment with SMT C1100 To investigate the relationships between changes in pulmonary function tests with plasma concentrations of SMT C1100 and its metabolites in paediatric subjects with DMD, following treatment with SMT C1100
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients will be required to satisfy the following criteria at the screening visit: 1. Be able to provide written informed consent/assent as per local requirements. 2. Be male. 3.Be aged ≥5 years <10 years of age (from 5th birthday to 10th birthday)-not applicable for cohort 3 4. Have phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (e.g., proximal muscle weakness, waddling gait, and Gowers' manoeuvre), an elevated serum creatinine kinase level, and ongoing difficulty with walking. 5. Have prior confirmation of the DMD diagnosis through:Documentation of the presence of a mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by the College of American Pathologists, the Clinical Laboratory Improvement Act/Amendment or an equivalent organization. Or Documentation of the absence of dystrophin in the muscle (via biopsy). 6. Be willing and able to comply with two muscle biopsy procedures (not applicable for cohort 3) 7. Be able to undergo MRI examination. 8. Patients must have used stable systemic corticosteroids (prednisone, prednisolone or deflazacort) for a minimum of 6 months immediately prior to the start of the Treatment Phase , with no significant change in dosage or dosing regimen (not related to body weight change) and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study. 9. Have the ability to walk at least 300 meters unassisted during the screening 6MWD and be below the protocol-specified threshold for 80%-predicted 6MWD (not applicable for cohort 3) 10. Have results of two 6MWD at Baseline determined as valid. The results of the second 6MWD must be within 20% of the first 6MWD (not applicable for cohort 3) 11. Have cardiac ECHO measurements showing an ejection fraction of ≥ 55% and fractional shortening of ≥28% (not applicable for cohort 3) 12. Confirmed screening laboratory values within the central laboratory ranges (haematology, renal and serum electrolyte parameters and serum chemistry parameters) or considered not clinically significant in the opinion of the Investigator. Variations in specific parameters expected in a DMD population (e.g., aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and creatinine phosphokinase) classed by the Investigator as not clinically significant will not exclude the patient 13. Be willing and able to comply with scheduled visits, drug administration plan, study procedures, laboratory tests and study restrictions. 14.Have taken part in a prior SMT C1100 study (not applicable for cohorts 1 and 2 ) |
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E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they satisfy the following criteria at the screening visit 1. Have physical exam findings that in the investigator’s opinion should be exclusionary e.g., lower limb injury that may affect 6MWD performance. 2. Have any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to the start of study treatment. 3. Have uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D). 4.Have abnormal GLDH at baseline (>1.5 x ULN) 5.Have abnormal coagulation times at baseline (>1.5 x ULN) 6. Have an abnormal ECG e.g., a QTcF >500ms, left bundle-branch block or any other major conduction defect. 7. Use beta blockers (however, if during the course of the study they are clinically indicated they can be initiated; not applicable for cohort 3 ) 8. Use herbal supplements and be unwilling to stop these for the duration of the study. 9. Have a known hypersensitivity to any of the ingredients or excipients of the IMP. (microfluidised oral suspension F3, cohort 1 : Poloxamer 188, Methylparaben, Propylparaben, Hydroxypropylmethyl cellulose, Glycerol, Non crystallizing sorbitol [70%], Xanthan gum, Strawberry cream flavour [PHS-132963]); 10.Have a known hypersensitivity to any of the ingredients or excipients of the IMP. Powder for oral suspension (F6): hypromellose acetate (not applicable to cohorts 1 and 3 ) 11. Have been exposed to another investigational drug or DMD interventional agent within 3 months prior to start of the Treatment Phase. Prior exposure to SMT C1100 or participation in an approved deflazacort access program (e.g FOR-DMD or ACCESS DMD clinical trials ) within this period would not exclude the patient (provided they have been on stable treatment for 6 months ) 12. Have a history of major surgical procedure within 12 weeks prior to the start of the Treatment Phase (week 1) 13. Be undertaking ongoing immunosuppressive therapy (other than corticosteroids). 14. Have an expectation of a major surgical procedure (e.g., scoliosis surgery) during the 12-month Treatment Phase of the study. 15. Require daytime ventilator assistance. 16. Have a prior or ongoing medical condition (e.g., concomitant illness, psychiatric condition, behavioural disorder, alcoholism, drug abuse), medical history, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results. 17. Be dairy or lactose intolerant or have any other dietary restrictions that might interfere with the conduct of the study. 18. Be a smoker, use other tobacco or nicotine products or be exposed to daily passive smoking (including parent/legal guardian, siblings) so as to minimize environmental factors causing CYP1A induction. 19.Be using an approved DMD medication or anticipates using one during the duration of the study e.g., ataluren, idebenone, drisapersen, Exondys51. Patients who are taking part in the FOR-DMD and ACCESS DMD studies may be allowed to take part. 20 Be using an inducer of CYP1A1, CYP1A2 . 21. Be using a substrate of CYP2B6. 22. All prescription, OTC, and herbal products that are known CYP2B6 sensitive substrates (e.g., buproprion, efavirenz) will be excluded 14 days prior to study conduct (beginning at sceening) through 14 days after study conduct completion. Please note, this is not an exhaustive list of CYP2B6 substrates and a discussion with the Medical Monitor may be warranted 23.Be using drugs that have serotonergic, norepinephrinergic or dopaminergic activity (e.g., selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, tryptophan, dextromethorphan, meperidine, bupropion, nortriptyline, desipramine, doxepin, amoxapine, rasagiline, selegiline), or treatments used in attention deficit hyperactivity disorder such as Methylphenidate, and phenethylamine (PEA). 24.Use of substrates of breast cancer resistance protein (e.g., omeprazole, rabeprazole, fluvastatin, methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline to Weeks 12, 24, 36 and 48 in MRI leg muscles parameters(Cohorts 1 and 2)
SMT C1100 and metabolite plasma concentrations at Weeks 1 (Days 1 and 7) as applicable (Cohorts 2 and 3 only) 4, 8 (Cohorts 1 and 2 only), 12, 24, 36 and 48
• Safety data including: Treatment emergent AEs
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline to Weeks 12, 24, 36 and 48 |
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E.5.2 | Secondary end point(s) |
Change from baseline to Week 24 or 48 in utrophin expression via muscle biopsy analysis (Cohorts 1 and 2) • Change from baseline to Week 24 or 48 in muscle regeneration biomarkers, via muscle biopsy analysis(Cohorts 1 and 2) • Change from baseline to Weeks 12, 24, 36 and 48 (Cohorts 1 and 2) and from baseline to Weeks 1, 24 and 48 (Cohort 3) in pulmonary function tests • Safety data including: • Vital signs (systolic and diastolic blood pressure and heart rate) • Physical examination • Twelve-lead electrocardiogram (ECG) • Echocardiogram (ECHO) • Pulmonary function tests (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC] maximum inspiratory pressure [MIP], maximum expiratory pressure [MEP] and peak expiratory flow [PEF]);Peak cough flow (PCF) (Cohort 3)Sniff nasal inspiratory pressure (SNIP) (Cohort 3
• Safety laboratory evaluations (clinical chemistry, haematology (all 3 cohorts) coagulation (Cohort 2 and Cohort 3) parameters and urinalysis (all 3 cohorts) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline to Week 24 or 48 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |